This is a multifaceted, multidisciplinary, interdepartmental and coordinated investigation to obtain a better understanding of the etiology and pathogenesis of and to explore possible improved therapeutic approaches which might be applied to small cell carcinoma of the lung in humans. We will continue and expand a spectrum of studies which will lead to a better understanding of the basic pathobiology of the putative cell of origin and of the tumor and develop an experimental model of this disease. Long-term cultures of the human tumor already have been established and are currently available for a wide variety of experimental studies. Studies on the growth of these tumors in nude mice and use for various therapeutic protocols are planned. Since small cell cultures produce a wide variety of peptide as well as steroid hormones, we will study the regulatory factors which are involved in the synthesis and secretion of these hormones as compared with normal cells. Calcitonin and bombesin secretion are influenced by cations, e.g., K+ and Ca+ concentration, cyclic AMP and acetylcholine. The use of multiple cholinergic agonists and antagonists has demonstrated the presence of muscarinic-type acetylcholine receptors on small cell carcinoma cells. We will evaluate certain parameters in patients, e.g., cell kinetics, which then would be compared with those of the cells from the same tumor established in culture and those of cells grown in nude mice. We also plan to evaluate a certain limited number of hormones, particularly "big" ACTH, as tumor markers and relate these values to tumor mass in patients throughout the clinical course, and particularly in relationship to therapeutic response. In addition, we will evaluate chromosomal abnormalities, which are associated with these tumors, and their persistence or alterations that may occur with time.